cblc137 and Lung-Neoplasms

Small cell lung cancer (SCLC) is characterised by high relapse rates. Tumour-initiating cells (TICs) are responsible for drug resistance and recurrence of cancer. Rovalpituzumab tesirine (Rova-T), a potent humanised antibody-drug conjugate, selectively targets delta-like protein 3, which is highly expressed in SCLC TICs. The experimental drug CBL0137 (CBL) inhibits the histone chaperone FACT (facilitates chromatin transcription), which is required for the expression of transcription factors that are essential for TIC maintenance. Rova-T and CBL each target SCLC TICs as single agents. However, acquired or intrinsic resistance to single agents is a major problem in cancer. Therefore, we investigated the potential effect of combining Rova-T and CBL in SCLC to eradicate TICs more effectively. Our preclinical studies report a novel and highly translatable therapeutic strategy of dual targeting TICs using Rova-T in combination with CBL to potentially increase survival of SCLC patients.

Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzodiazepinones; Carbazoles; Cell Proliferation; Drug Resistance, Neoplasm; Humans; Immunoconjugates; Lung Neoplasms; Mice; Mice, Inbred NOD; Mice, SCID; Prognosis; Small Cell Lung Carcinoma; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Suppressor of Ty 16 (Spt16) is a component of the facilitates chromatin transcription (FACT) complex, which is a histone chaperone and involved in gene transcription, DNA replication, and DNA repair. Previous studies showed that FACT is highly expressed in cancer, and cancer cells are more reliant on FACT than normal cells. However, the relationship between Spt16 and lung cancer remains unclear. In this study, we explored the functions of Spt16 in lung cancer cells. The effects of Spt16 on lung cancer cell proliferation, cell cycle progression, apoptosis, migration, and invasion were examined. We found that knockdown of Spt16 led to obvious decreases of both Rb and MCM7, and further activated the DNA damage response (DDR) pathway. In addition, a novel micro-RNA, miR-1227-5p, directly targeted the 3'-UTR of Spt16 and regulated the mRNA levels of Spt16. Furthermore, we found that CBL0137, the functional inhibitor of FACT, showed similar effects as loss of Spt16. Together, our data indicated that Spt16 is likely to be an essential regulator for lung cancer malignancy and is negatively regulated by miR-1227-5p.

Topics: 3' Untranslated Regions; Apoptosis; Carbazoles; Cell Cycle; Cell Cycle Proteins; Chromatin; Disease Progression; DNA Damage; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Lung Neoplasms; MicroRNAs; Neoplasm Grading; RNA Interference; Transcription Factors; Transcription, Genetic

Cancer cell repopulation through cell cycle re-entry by quiescent (G

Topics: A549 Cells; Carbazoles; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p27; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; High Mobility Group Proteins; Humans; Lung Neoplasms; Male; PC-3 Cells; Prostatic Neoplasms; Resting Phase, Cell Cycle; Transcriptional Elongation Factors

Traditional treatments of small-cell lung cancer (SCLC) with cisplatin, a standard-of-care therapy, spare the tumor-initiating cells (TIC) that mediate drug resistance. Here we report a novel therapeutic strategy that preferentially targets TICs in SCLC, in which cisplatin is combined with CBL0137, an inhibitor of the histone chaperone facilitates chromatin transcription (FACT), which is highly expressed in TICs. Combination of cisplatin and CBL0137 killed patient-derived and murine SCLC cell lines synergistically. In response to CBL0137 alone, TICs were more sensitive than non-TICs, in part, because CBL0137 increased expression of the tumor suppressor

Topics: Animals; Carbazoles; Cell Line, Tumor; Cell Self Renewal; Cell Survival; Cisplatin; Disease Models, Animal; DNA-Binding Proteins; Drug Synergism; High Mobility Group Proteins; Humans; Lung Neoplasms; Neoplastic Stem Cells; Receptor, Notch1; Signal Transduction; Small Cell Lung Carcinoma; Transcriptional Elongation Factors; Xenograft Model Antitumor Assays